Cuparene

The AE reactions on 2,5,5-trisubstituted allyl alcohols have received little attention, due in part the limited utility of the product epoxides. Selective ring opening of tetrasubstituted epoxides are difficult to achieve. Epoxide 39 was prepared using stoichiometric AE conditions and were subsequently elaborated to Darvon alcohol. Epoxides 40 and 41 were both prepared in good selectivity and subsequently utilized in the preparation of (-)-cuparene and the polyfunctoinal carotenoid peridinin, respectively. Scheme 1.6.12... 

Despite the favorable thermodynamics associated with the cyclization of unsaturated organolithiums, the isomerization is often sluggish when the ring closure involves generation of a quaternary center or formation of a strained framework. In such cases it has been found that addition of lithiophilic Lewis bases such as THF or TMEDA facilitate the reaction.7 9 The preparation of cuparene, a sterically congested sesquiterpene possessing two adjacent quaternary centers, illustrates the methodology.11... 

For synthesis of the sesquiterpene ( )-cuparene (2-358) [192] using this method, 2-355 was reacted with 2-354 and 2-356 to give 2-358 via 2-357 in 45 /o overall yield. 

Grainger s group has developed an asymmetric route to (-)-cuparene (5-83) [22] using another photoinduced generation of a biradical (Scheme 5.16) [23]. Thus, irradiation of (S)-proline-derived 5-80 resulted initially in the formation of 5-81, which subsequently cyclizes in almost quantitative yield to afford a mixture of the four possible diastereomers 5-82a-d in an approximate 10 5 2 1 ratio. The two major isomers could be separated by column chromatography to provide 5-82a in 36% yield and the desired 5-82b in 55 %, which was converted into the natural product 5-83 in 24% yield over three steps. 

Dipolar cycloaddition. Arylthiomethyl chlorides (1) in the presence of a Lewis acid can undergo a [4 + 2]cycloaddition to a tetrasubstituted alkene. They can be prepared by reaction of thiophenol with BrCH2Cl in the presence of DBU in CH,CN. C2H5A1C12 is preferred over A1C1, SnCl4, or TiCl4 as the Lewis acid. This reaction provides a short synthesis of cuparene (2). 

Kladi M, Vagias C, Fumari G, Moreau D, Roussakis C, Rousis V (2005) Cytotoxic Cuparene Sesquiterpenes from Laurencia microcladia. Tetrahedron Lett 46 5723... 

Mao S-C, Guo Y-W (2005) Cuparene-Derived Sesquiterpenes from the Chinese Red Alga Laurencia okamurai Yamada. Helv Chim Acta 88 1034... 

Several members of the Cuparene class of sesquiterpenoids show interesting biological activity, including potent antifungal, neurotrophic and lipid peroxidation inhibition activity. Moreover, the presence of a hindered, quaternary... 

Scheme 9 Photomediated and microwave-assisted synthesis of Cuparene...

Cuparene 244 contains two adjacent quaternary centres, and by adding TMEDA Bailey was able to make it in 76% yield from 243.126 Although the standard conditions for halogen-metal exchange employ two equivalents of f-BuLi, in this case it turned out that the second equivalent added directly to the styrene double bond.127 One equivalent turned out to give acceptable yields. 

When the alkene trap is 1,1-disubstituted, cyclisation of a tertiary benzylic organolithium gives a product with two adjacent quaternary centres. Krief applied this type of cyclisation to the synthesis of cuparene 244136 using a different disconnection from the one used by Bailey (above). Though it is irrelevant to the synthesis of cuparene, the cyclisation of 257 to 258 is also stereoselective and produces a single stereoisomer of 259 on carbonation of the cyclised organolithium. The tertiary organolithium is too basic to cyclise in THF and in this solvent... 

Cuparene (76) has been synthesized by a simple route (Scheme 14) in which the five-membered ring is constructed by photocyclization of an appropriate thioketone (75).37... 

The isolation of -(-)-cuparene (77), and f -(-)-S-cuparenol (78) from the liverwort, Bazzania pompeana, is consistent with the general tendency of this type of plant to produce sesquiterpenoids enantiomeric with those found in higher plants38... 

A large number of tertiary alkyl chlorides has been methylated. Equations 77-79 are typical41,74). The simple synthesis of (i)-cuparene 252 is an application in terpene chemistry 35). 

A novel radical anion (LDMAN) methodology developed by Cohen and coworkers (see Section IILA.2) was then applied efficiently for the two-pot synthesis of the sesquiterpene ( )-cuparene, 184, starting from the allyl reagent 180118. The tandem addition/cyclization... 

In this context Cohen and coworkers have reported that a homoaflyllithium, generated by reductive lithiation (see below) from phenyl thioether 153, adds to a-methylstyrene and the resulting benzyllithium is able to cyclize, giving rise to sesquiterpene ( )-cuparene (Scheme 43)77. 

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